Betamimetics (β-adrenergic substances) are known from the prior art. For example reference may be made in this respect to the disclosure of U.S. Pat. No. 4,460,581, which proposes betamimetics for the treatment of a range of diseases.
For drug treatment of diseases it is often desirable to prepare medicaments with a longer duration of activity. As a rule, this ensures that the concentration of the active substance in the body needed to achieve the therapeutic effect is guaranteed for a longer period without the need to re-administer the drug at frequent intervals. Moreover, giving an active substance at longer time intervals contributes to the well-being of the patient to a high degree.
It is particularly desirable to prepare a pharmaceutical composition which can be used therapeutically by administration once a day (single dose). The use of a drug once a day has the advantage that the patient can become accustomed relatively quickly to regularly taking the drug at certain times of the day.
The enantiomerically pure compound according to formula 1 is a long-acting betamimetic.
Compound 1 used as a medicament for the treatment of respiratory complaints is preferably administered by inhalation. Suitable inhalable powders packed into appropriate capsules (inhalettes) may be administered using corresponding powder inhalers. Alternatively they may be administered by the use of suitable inhalable aerosols. These also include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellant gas.
The correct manufacture of the abovementioned compositions which may be used for the administration by inhalation of a pharmaceutical active substance is based on various parameters connected with the nature of the pharmaceutical active substance itself. Without being restricted thereto, examples of these parameters are the stability of effect of the starting material under different ambient conditions, the stability during the manufacture of the pharmaceutical formulation and the stability in the finished compositions of the pharmaceutical substance. The active substance used to prepare the pharmaceutical compositions mentioned above should be as pure as possible, and its stability during long-term storage should be guaranteed under a variety of ambient conditions. This is absolutely essential to prevent the use of pharmaceutical compositions which contain breakdown products of the active substance as well as the active substance itself. In such a case the content of active substance in a capsule might be lower than specified.
The absorption of moisture reduces the content of pharmaceutically active substance on account of the weight gain caused by the uptake of water. Pharmaceutical compositions with a tendency to absorb moisture have to be protected from damp during storage, e.g. By the addition of suitable drying agents or by storing the medicament in a damp-proof environment. In addition, the uptake of moisture can reduce the content of pharmaceutically active substance during manufacture if the medicament is exposed to the environment without being protected from damp in any way.
Uniform distribution of the medicament in the formulation is also a critical factor, particularly when the medicament has to be given in low doses. To ensure uniform distribution, the particle size of the active substance can be reduced to a suitable level, e.g. by grinding. Another aspect which is important in active substances to be administered by inhalation by means of a powder arises from the fact that only particles of a certain size can be taken into the lungs by inhalation. The particle size of these lung-bound particles (inhalable fraction) is in the range between 2 and 5 μm. In order to obtain active substances of a corresponding particle size, a grinding process (so-called micronising) is again required.
Since breakdown of the pharmaceutically active substance as a side effect of the grinding (or micronising) has to be avoided as far as possible, in spite of the hard conditions required during the process, it is absolutely essential that the active substance should be highly stable throughout the grinding process. Only if the active substance is sufficiently stable during the grinding process is it possible to produce a homogeneous pharmaceutical formulation which always contains the specified amount of active substance in reproducible manner.
A specific problem which may arise in the grinding process for preparing the desired pharmaceutical formulation is the input of energy caused by this process and the stress on the surface of the crystals. This may in certain circumstances lead to polymorphous changes, to a change in the amorphous configuration or to a change in the crystal lattice. Since the pharmaceutical quality of a pharmaceutical formulation requires that the active substance should always have the same crystalline morphology, the stability and properties of the crystalline active substance are subject to stringent requirements from this point of view as well.
A particularly important aspect that has to be taken into consideration according to the invention is that, as the specific surface area increases, as happens automatically during micronisation, the surface energy of a particulate system also increases accordingly. As each system tends towards a minimum energy, from the thermodynamic point of view, for particulate systems that have an inhalable particle size and hence a specific surface area of typically between 1 m2/g and 10 m2/g, high demands are made of the crystallinity of the micronised pharmaceutical active substance. It should be noted that crystalline order is thermodynamically preferable to disordered systems and hence crystalline particulate systems are physically more stable from a thermodynamic point of view, particularly when the specific crystal structure is especially stable compared with other crystal structures from a thermodynamic point of view.
The invention therefore sets out in particular to solve the problem of providing a thermodynamically particularly stable form of the compound of formula 1.